Condensed azepines as vasopressin agonists

ABSTRACT

This invention provides novel compounds according to general formula (1) wherein A is a bicyclic or tricyclic azepine derivative, V 1  and V 2  are both H, OMe or F, or one of V 1  and V 2  is Br, Cl, F, OH, OMe, OBn, OPh, O-acyl, N 3 , NH 2 , NHBn or NH-acyl and the other is H, or V 1  and V 2  together are ═O, —O(CH 2 ) p O— or —S(CH 2 ) p S—; W 1  is either O or S; X 1  and X 2  are both H, or together are ═O or ═S; Y is OR 5  or NR 6 R 7 ; R 1 , R 2 , R 3  and R 4  are independently selected from H, lower alkyl, lower alkyloxy, F, Cl and Br; R 5  is selected from H and lower alkyl; R 6  and R 7  are independently selected from H and lower alkyl, or together are —(CH 2 ) n —; n=3, 4, 5, 6; and p is 2 or 3. The compounds are agonists at the vasopressin V2 receptor and are useful as antidiuretics and procoagulants. The invention further comprises pharmaceutical compositions incorporating these vasopressin agonists, which compositions are particularly useful in the treatment of central diabetes insipidus, nocturnal enuresis and nocturia.

This application is a national stage entry under 35 U.S.C. § 371 ofPCT/GB01/00023, filed Jan. 4, 2001.

FIELD OF INVENTION

The present invention relates to a class of novel chemical entitieswhich act as agonists of the peptide hormone vasopressin. They reduceurine output from the kidneys and so are useful in the treatment ofcertain human diseases characterised by polyuria. They are also usefulin the control of urinary incontinence and bleeding disorders.

BACKGROUND TO THE INVENTION

Vasopressin is a peptide hormone secreted by the posterior pituitarygland. It acts on the kidney to increase water retention and so reduceurine output. For this reason, vasopressin is alternatively known as“antidiuretic hormone”. It also acts on the vasculature, where itproduces a hypertensive effect. The cellular receptors that mediatethese two actions have been characterised and shown to be different. Theantidiuretic action is mediated by the type-2 vasopressin receptor,commonly called the V₂ receptor. Agents that can interact with the V₂receptor and activate it in the same way as vasopressin are called V₂receptor agonists (or simply V₂ agonists). Such agents will have anantidiuretic action. If these agents interact selectively with the V₂receptor and not the other vasopressin receptor subtypes, then they willnot have the hypertensive effect of vasopressin. This would be animportant safety consideration and make such agents attractive for thetreatment of human disease conditions characterised by polyuria (whichis herein taken to mean excessive urine production).

In fact, such an agent is already in use in human therapy. Desmopressin(otherwise [1-desamino, D-Arg⁸]vasopressin, Minirin™, DDAVP™) is apeptide analogue of vasopressin which is selectively an agonist at theV₂ receptor. It is used in the treatment of central diabetes insipidus,which is a condition that results from defective secretion ofvasopressin. It is also employed in the control of nocturnal enuresisand may also be of use in the control of nocturia. However, desmopressinis not an ideal agent in all respects. Even the best current synthesesof the agent are lengthy, and desmopressin is not amenable to the mostconvenient of purificaton techniques such as crystallisation.Consequently, desmopressin is relatively expensive. It has a very loworal bioavailability, and there is some variability in this parameter.

Overall then, there exists a need for a selective vasopressin V₂receptor agonist that is easy to prepare and purify, and that has a highand predictable oral bioavailability. Such properties are most likely tobe obtained with a non-peptide compound. These considerations have ledother groups to investigate non-peptide vasopressin V₂ agonists, andtheir results are disclosed in, for example, International PatentApplications WO97/22591, WO99/06403, WO99/06409, WO00/46224, WO00/46225,WO00/46227 and WO00/46228. The compounds disclosed in these documentsare, however, less than ideal. In particular, they have poor oralbioavailability, probably due in part to their low aqueous solubility.The present invention provides compounds with improved solubility andbloavailability.

Besides its antidiuretic actions, desmopressin is used to increase theconcentration in the blood of the coagulation proteins known as FactorVIII and von Willebrand factor. In the clinical context, this makesdesmopressin useful in the treatment of haemophilia A and vonWillebrand's disease. Similar applications would be open to thenon-peptide agonists of the present invention.

SUMMARY OF THE INVENTION

As disclosed herein, the present invention relates to a series ofcompounds that are non-peptide agonists of vasopressin and which areselective for the V₂ receptor subtype. The compounds are described bygeneral formula 1

wherein:

-   -   A is a bicyclic or tricyclic azepine derivative selected from        general formulae 2 to 7

-   -   A¹, A⁴, A⁷ and A¹⁰ are each independently selected from CH₂, O        and NR⁸;    -   A², A³, A⁹, A¹¹, A¹³, A¹⁴ and A¹⁵ are each independently        selected from CH and N;    -   either A⁵ is a covalent bond and A⁶ is S, or A⁵ is N═CH and A⁶        is a covalent bond;    -   A⁸ and A¹² are each independently selected from NH and S;    -   A¹⁶ and A¹⁷ are both CH₂, or one of A¹⁶ and A¹⁷ is CH₂ and the        other is selected from O, SO_(x), and NR⁸,    -   V¹ and V² are both H, OMe or F, or one of V¹ and V² is Br, Cl,        F, OH, OMe, OBn, OPh, O-acyl, N₃, NH₂, NHBn or NH-acyl and the        other is H, or V¹ and V² together are ═O, —O(CH₂)_(p)O— or        —S(CH₂)_(p)S—;    -   W¹ is either O or S;    -   X¹ and X² are both H, or together are ═O or ═S;    -   Y is OR⁵ or NR⁶R⁷;    -   Z is S or —CH═CH—;    -   R¹, R², R³ and R⁴ are independently selected from H, lower        alkyl, lower alkyloxy, F, Cl and Br;    -   R⁵ is selected from H and lower alkyl;    -   R⁶ and R⁷ are independently selected from H and lower alkyl, or        together are —(CH₂)_(n)—;    -   R⁸ is H or lower alkyl;    -   n=3, 4, 5 or 6;    -   p is 2 or 3; and    -   x is 0, 1 or 2.

The invention further comprises pharmaceutical compositionsincorporating these vasopressin agonists, which compositions areparticularly useful in the treatment of central diabetes insipidus,nocturnal enuresis and nocturia.

DESCRIPTION OF THE INVENTION

The present invention comprises N-benzylcarbamyl pyrrolidine derivativesdefined by general formula 1.

In this formula, A represents a bicyclic or tricyclic azepine groupaccording to one of the general formulae 2–7.

-   A¹, A⁴, A⁷ and A¹⁰ represent divalent groups selected from methylene    (—CH₂—), oxygen (—O—) and substituted nitrogen (—NR⁸—). A², A³, A⁹,    A¹¹, A¹³, A¹⁴ and A¹⁵ represent either a nitrogen atom (—N═) or a    methine group (—CH═). A⁵ can represent a covalent bond, in which    case A⁶ represents a sulphur atom (—S—) such that the ring that    includes these two groups is a thiophene ring. Alternatively, A⁵ can    represent a group —N═CH—, in which case A⁶ represents a covalent    bond such that the ring that includes these two groups is a pyridine    ring. A⁸ and A¹² represent either —NH— or a sulphur atom (—S—). A¹⁶    and A¹⁷ represent divalent groups. Both may be methylene groups    (—CH₂—) or one is a methylene group and the other is selected from    hydroxymethylene (—CH(OH)—), difluoromethylene (—CF₂—), oxygen    (—O—), substituted nitrogen (—NR⁶—) and sulphur or oxidised sulphur    (—S—, —SO—, or —SO₂—).-   V¹ and V² may both be hydrogen, methoxy or fluorine, or one may be    selected from bromine, chlorine, fluorine, hydroxy, lower alkoxy,    benzyloxy, phenoxy, acyloxy, azido, amino, benzylamino and acylamido    (Br, Cl, F, OH, O-lower alkyl, OBn, OPh, O-acyl, NH₂, NHBn and    NH-acyl) provided that the other is hydrogen, or V¹ and V² together    may represent an oxygen atom such that the fragment CV¹V² is a    carbonyl group (C═O). V¹ and V² may also be an ethylene- or    propylene-dioxy or -dithio chain (—O(CH₂)₂O—, —O(CH₂)₃O—,    —S(CH₂)₂S—, —S(CH₂)₃S—) such that CV¹V² is a 1,3-dioxolane,    1,3-dioxane, 1,3-dithiolane or 1,3 dithiane ring.-   W¹ is either an oxygen or a sulphur atom.-   X¹ and X² may either both be hydrogen, or together they may    represent an oxygen or sulphur atom such that the fragment CX¹X² is    a carbonyl or thiocarbonyl group (C═O or C═S).-   Y is either a group —OR⁵ or a group —NR⁶R⁷.-   Z represents either a sulphur atom, such that the ring that includes    it is a thiophene ring, or it represents a group —CH═CH—, such that    the ring is a benzene ring.-   R¹, R², R³ and R⁴ are each independently selected from hydrogen,    lower alkyl groups, lower alkyloxy groups and the halogens fluorine,    chlorine and bromine.-   R⁵ may be either a hydrogen atom or a lower alkyl group.-   R⁶ and R⁷ may each independently be hydrogen atoms or lower alkyl    groups, or together they may constitute a chain of between 3 and 6    methylene groups such that, together with the nitrogen atom to which    they are attached, they form an azetidine, pyrrolidine, piperidine    or perhydroazepine ring.-   R⁸ may be hydrogen or a lower alkyl group.

In the context of the present disclosure, the term “lower alkyl” isintended to include straight chain and branched alkyl groups andcycloalkyl groups of between 1 and 6 carbon atoms. For example, methyl,ethyl, isopropyl, tert-butyl, neopentyl and cyclohexyl are all withinthe scope of the term lower alkyl. The term “acyl” denotes lower alkylcarbonyl groups such as acetyl, pivaloyl, cyclopropylcarbonyl and thelike. Formyl is also considered to be an acyl group.

Certain compounds of general formula 1 are capable of forming salts withacids or bases. For example, compounds containing one or more nitrogenatoms can form addition salts with mineral and organic acids such ashydrochloric acid, sulphuric acid, phosphoric acid, acetic acid,trifluoroacetic add, methanesulphonic acid, citric acid and benzoicacid. Compounds containing acidic groups can form salts with bases.Examples of such salts include the sodium, potassium, calcium,triethylammonium and tetraethylammonium salts. Furthermore, compoundsthat have both acidic and basic groups can form internal salts(zwiterions). Insofar as these salts are pharmaceutically acceptable,they are included within the scope of the invention.

The compounds according to general formula 1 all have at least onestereogenic centre (a tetrahedral carbon atom bearing four differentsubstituents) and so can exist as optical isomers such as enantiomersand diastereomers. Such isomers, and mixtures thereof, are all intendedto be within the scope of the present invention.

In a preferred embodiment of the present invention, A is a groupaccording to general formula 2. In another preferred embodiment of thepresent invention, A is a group according to general formula 3. Inanother preferred embodiment of the present invention, A is a groupaccording to general formula 4. In another preferred embodiment of thepresent invention, A is a group according to general formula 5. Inanother preferred embodiment of the present invention, A is a groupaccording to general formula 6.

In another preferred embodiment of the present invention, A is a groupaccording to general formula 7. In a more preferred embodiment, A is atetrahydro-1-benzazepin-1-yl group, i.e. a group according to generalformula 7 in which Z is —CH═CH— and both A¹⁶ and A¹⁷ are methylenegroups.

In another preferred embodiment, one of R¹ and R² is chlorine or amethyl group and the other is hydrogen, with both R³ and R⁴ also beinghydrogen.

In another preferred embodiment, one of V¹ and V² is a methoxy orbenzyloxy group and the other is hydrogen.

In yet another preferred embodiment, X¹ and X² together represent anoxygen atom and Y is —NR⁶R^(7.)

Particularly preferred embodiments of the present invention are thosethat combine two or more of the above preferred features.

A still more preferred embodiment of the present invention is a compoundaccording to general formula 8.

In general formula 8, W¹, R⁵ and R⁶ are as defined above for 1. One ofR^(a) and R_(b) is hydrogen and the other is either chlorine or a methylgroup. R^(c) is either a methyl group or a benzyl group.

A yet more preferred embodiment is a compound of general formula 8A inwhich the stereochemistry is as shown.

Another preferred embodiment of the present invention is a compoundaccording to general formula 1 in which V¹ and V² are both hydrogen. Ina more preferred embodiment, X¹ and X² together are an oxygen atom and Yis NR⁶R⁷. More preferred still is a compound according to generalformula 9.

In general formula 9, W¹, R⁵ and R⁶ are as defined above for 1. One ofR^(a) and R^(b) is hydrogen and the other is either chlorine or a methylgroup.

Even more preferred is a compound according to general formula 9A inwhich the stereochemistry is as shown.

Individual preferred compounds within the present invention include (butare not limited to) the following:

-   1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide,-   (4R)-4-hydroxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide,-   (4R)-1-(3-chloro-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-4-methoxy-L-proline-N,N-dimethylamide,-   (4R)-1-(2-chloro-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-4-methoxy-L-proline-N,N-dimethylamide,-   (4R)-4-benzyloxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide,-   (4R)-4-methoxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide,-   (4R)-4-methoxy-1-(3-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide,-   (4R)-1-(2-chloro-4-(5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepin-4-ylcarbonyl)benzylcarbamoyl)-4-methoxy-L-proline-N,N-dimethylamide,-   (4R)-1-(4-(10,11-dihydro-5H-pyrrolo[2,1-c](1,4)benzodiazepin-10-ylcarbonyl)-2-methyl-benzylcarbamoyl)-4-methoxy-L-proline-N,N-dimethylamide,-   (4R)-1-(2-chloro-4-(10,11-dihydro-5H-pyrrolo[2,1-c](1,4)benzodiazepin-10-ylcarbonyl)benzylcarbamoyl)-4-methoxy-L-proline-N,N-dimethylamide,    and-   (4R)-1-(4-(10,11-dihydro-5H-pyrrolo[2,1-c](1,4)benzodiazepin-10-ylcarbonyl)-2-methyl-benzylcarbamoyl)-4-methoxy-L-proline-N,N-dimethylthioamide.

The compounds of the present invention can be prepared using methodsgenerally known in the art. The compounds of general formula 1 can beconsidered to be composed of three linked fragments (A–C).

The three fragments will generally be prepared separately and thencombined at a late stage in the synthesis. Some instances of the variousgroups (R¹–R⁴, V¹, V², X¹, X² etc.) might be incompatible with thisassembly and so will require the use of protecting groups. The use ofprotecting groups is well known in the art (see for example “ProtectiveGroups in Organic Synthesis”, T. W. Greene, Wiley-Interscience, 1981).Particular groups that may require protection are amines (protected asamides or carbamates), alcohols (protected as esters or ethers) andcarboxylic acids (protected as esters). For the purposes of thisdiscussion, it will be assumed that such protecting groups as arenecessary are in place.

The fragments A, B and C can be combined according to two strategies togive the compounds of formula 1. In the first, fragments A and B arelinked to give a fragment corresponding to AB, which is then combinedwith fragment C. In the second, fragments B and C are linked to give afragment corresponding to BC, which is then combined with fragment A.The chemistry involved in the condensation of fragment A with B, andthat involved in the condensation of fragment B with fragment C, will bethe same whichever strategy is followed. We have found that the firststrategy is more flexible when working on a small scale and forpreparing a selection of compounds. Nevertheless, it is possible thatthe second strategy would be advantageous for the preparation of aselected compound on a large scale.

Formation of Fragment AB

Here, {A} and {B} represent part structures of the fragments A and Brespectively. The formation of amides by the condensation of carboxylicacids with amines is well known. In general, the acid and the amine aremixed in an aprotic solvent such as dichloromethane or dimethylformamidein the presence of a condensing agent such as a carbodiimide (forexample “water-soluble carbodiimide”, which isN-ethyl-N-(3-dimethylaminopropyl)-carbodiimide) or a reactive phosphorusderivative (for example “BOP”, which is(benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate). The reaction may optionally be catalysed by atertiary amine such as triethylamine or 4-dimethylaminopyridine.Alternatively, the carboxylic acid may be converted to a more reactivederivative such as the acid chloride. Such a derivative can then bereacted with the amine as described above but without the need for acondensing agent.

Formation of Fragment BC

Formation of the urea or thiourea bond between fragments B and C can bemost easily achieved by allowing the primary amine corresponding tofragment B to react with a derivative of carbonic acid such as phogene(wherein LG above is chlorine) or carbonyidiimidazole (wherein LG is1-imidazolyl) to form an intermediate carbamic acid derivative. When W¹is sulphur rather than oxygen, thiophosgene or thiocarbonyldiimidazoleis used. The reaction is conveniently carried out in an aprotic solventsuch as dichloromethane or dimethylformamide in the presence of atertiary amine such as triethylamine or N,N-diisopropylethylamine. Afterallowing sufficient time for the formation of the intermediate, thesecondary amine corresponding to fragment C can be added to the reactionmixture. It is not necessary to isolate the intermediate carbamatederivative.

As a variation of this process, it is possible to reverse the order ofaddition of the amines corresponding to fragments B and C, such that thecarbamate derivative is formed from the secondary amine, and the primaryamine is added subsequently.

Overall then, the following intermediates are required for the synthesisof the compounds of the present invention

i) For Fragment A

Fused azepines according to these general formulae can be preparedaccording to methods reported in the literature. See for example:Aranapakam et al., Bioorg. Med. Chem. Lett. 1993, 1733; Artico et al.,Farmaco. Ed. Sci. 24, 1969, 276; Artico et al., Farmaco. Ed. Sci. 32,1977, 339; Chakrabarti et al., J. Med. Chem. 23, 1980, 878; Chakrabartiat al., J. Med. Chem. 23, 1980, 884; Chakrabarti et al., J. Med. Chem.32, 1989, 2573; Chimirri et al., Heterocycles 36, 1993, 601; Grunewaldet al., J. Med. Chem. 39, 1996, 3539; Klunder et al., J. Med. Chem. 35,1992, 1887; Liegéois et al., J. Med. Chem. 37, 1994, 519; Olagbemiro etal., J. Het. Chem. 19, 1982, 1501; Wright et al., J. Med. Chem. 23,1980, 462; Yamamoto et al., Tet. Lett. 24, 1983, 4711; and Internationalpatent application, publication number WO99/06403.

Some of them are Items of commerce.

ii) For Fragment B

Because the primary amine and the carboxylic acid groups areincompatible, they must be developed separately and protected.Substituted benzoic acids are well known, and the carboxylic acid isconveniently protected as its methyl ester. The primary amine can beelaborated from the corresponding nitrile (by reduction) or the alcohol(by displacement with a nitrogen nucleophile). The best method willdepend on the nature of the substituents R¹–R⁴.

iii) For Fragment C

Pyrrolidine derivatives of this type are prepared according to themethods described in the literature. See for example: Dugave et al.,Tet. Lett. 39, 1998, 1169; Petrillo et al., J. Med. Chem. 31, 1988,1148; and Smith et al., J. Med. Chem. 31, 1988, 875.

Proline and hydroxyproline derivatives of defined stereochemistry areitems of commerce and as such are convenient starting materials.

The present invention further comprises pharmaceutical compositions thatinclude at least one compound according to the foregoing description asan active constituent. The composition may also include a secondpharmacological agent such as a spasmolytic or a potassium channelblocker, these agents being known in the art to ameliorate bladderdysfunction. Preferably, the composition includes only one activeconstituent. The composition will include excipients selected frombinding agents, bulking agents, dispersants, solvents, stabilisingagents and the like, such excipients being generally known in the art.

The excipients used will depend on the intended nature of theformulation, which will, in turn, depend on the intended route ofadministration. Administration may be oral, transmucosal (such assublingual, buccal, intranasal, vaginal and rectal), transdermal or byinjection (such as subcutaneous, intramuscular and intravenous). Oraladministration is generally preferred. For oral administration, theformulation will be a tablet or capsule. Other formulations include drypowders, solutions, suspensions, suppositories and the like.

In a further aspect, the present invention is a method of treating orcontrolling certain human physiological dysfunctions. This methodcomprises the administration to the person in need of such treatment ofan effective amount of a pharmaceutical composition, which compositioncontains a compound according to the foregoing description as an activeconstituent. The compounds act to reduce urine output, and so the methodof the invention can be applied to all conditions in which elevatedurine output is a contributory factor. The compounds also increase theproduction of the blood coagulation proteins known as Factor VIII andvon Willebrand factor, and so the treatment of bleeding disorders can beundertaken.

In a preferred embodiment, the condition treated is diabetes insipidus.This is a condition caused by an inability of the body to produce andsecrete physiologically active vasopressin, with the result that waterre-uptake is greatly reduced and large volumes of urine are produced.

In another preferred embodiment, the condition treated is nocturnalenuresis. This is defined as bladder emptying while the individual issleeping. It is a condition that mainly affects children and a number offactors may be involved in its etiology.

In another preferred embodiment, the condition treated is nocturia. Thisis defined as production of sufficient urine during the night to requirethe individual to wake and empty his (or her) bladder. Again, thiscondition may be the result of a number of factors.

In another preferred embodiment, the condition treated is incontinence.This condition is characterised, in part, by reduced bladder capacityand control such that involuntary urination occurs unless the bladder isemptied frequently. Incontinence has been divided into two conditions,stress incontinence and urge incontinence. A number of etiologicalfactors are thought to be involved. Treatment according to the inventionis particularly useful for delaying the need for bladder emptying(“voiding postponement”) in order to allow the incontinent subject a dryperiod of a few hours (such as up to four hours). Such voidingpostponement may also be useful for the non-incontinent population, forexample for people obliged to remain in meetings for extended periods.

In another preferred embodiment, the condition treated is haemophilia Aor von Willebrand's disease. These are conditions in which Factor VIIIor von Willebrand factor production is reduced and the individualsuffers from prolonged bleeding.

In another preferred embodiment, the composition is administered priorto surgery (including dental surgery) to increase the coagulability ofthe blood and so reduce peri-operative blood loss.

The administration of the compositions of the present invention willgenerally be under the control of a physician. The physician willdetermine the amount of composition to be administered and the dosingschedule, taking into account the patient's physical condition and thetherapeutic goals. For an adult diabetes insipidus patient, a typicaldose might be between 50 mg and 1 g of the active compound per day,taken as a single tablet or as up to four tablets throughout the day.For routes of administration other than the oral route, the amount ofcompound will be reduced, since non-oral routes tend to be moreefficient in terms of delivering therapeutic agents into the systemiccirculation. For the treatment of haemophilia A and von Willebrand'sdisease the amount of compound may need to be higher than for thetreatment of diabetes insipidus.

The foregoing general description will now be further illustrated with anumber of non-limiting examples.

EXAMPLES

Abbreviations

The following abbreviations have been used.

Ac Acetyl AIBN Azo-bis-(isobutyronitrile) Bn Benzyl BOCtert-Butyloxycarbonyl (BOC)₂O Di-tert-butyl dicarbonate DMFDimethylformamide Et Ethyl EtOAc Ethyl acetate IPA Isopropanol iPrIsopropyl M.S. Mass spectrometry Me Methyl NBS N-Bromosuccinimide pet.ether petroleum ether, fraction boiling at 60–80° C. Ph Phenyl tButert-Butyl THF Tetrahydrofuran WSCDI Water-soluble carbodiimidePreparation of Intermediates

Reagents corresponding to fragment A and C were commercially availableor prepared according to the published procedures except where detailedin the specific Examples. Reagents corresponding to fragment B wereprepared as detailed below.

Example A 4-(tert-Butyloxycarbonylaminomethyl)-3-chlorobenzoic acid

A1. Methyl 4-bromomethyl-3-chlorobenzoate

To a solution of methyl 3-chloro-4-methylbenzoate (5.0 g, 27.1 mmol) incarbon tetrachloride (50 ml) were added NBS (5.8 g, 32.0 mmol) and AIBN(0.442 g, 2.70 mmol). The mixture was stirred at reflux for 18 h. Themixture was allowed to cool to room temperature and then concentrated invacuo. The residue was purified by flash chromatography on silica(eluant EtOAc:pet. ether 0:100 to 5:95); yield 5.96 g (84%).

A2. 4-(tert-Butyloxycarbonylaminomethyl)-3-chlorobenzoic acid

To a saturated solution of ammonia in ethanol (170 ml) was added methyl4-bromomethyl-3-chlorobenzoate from Example A1 (5.5 g, 20.9 mmol). Themixture was stirred at room temperature for 1 h and then concentrated invacuo. The residue was triturated with diethyl ether and the resultantwhite crystals were filtered off and washed with more diethyl ether. Toa solution of this solid in water (100 ml) were added solutions of(BOC)₂O (5.0 g, 23.0 mmol) in dioxan (100 ml) and sodium hydroxide (1.86g, 46.0 mmol) in water (100 ml). The mixture was stirred at roomtemperature for 18 h and then concentrated in vacuo. The aqueous residuewas acidified with citric acid and extracted with chloroform/IPA. Theorganic layer was washed with water, dried over MgSO₄, and concentratedin vacuo to give a white solid; yield 2.89 (67%).

Example B 4-Cyano-3-methylbenzoic acid

To a solution of 4-bromo-2-methylbenzonitrile (2.0 g, 10.2 mmol) in THF(100 ml) at −78° C. under a nitrogen atmosphere was added dropwise a2.5M solution of n-butyl lithium (4.48 ml, 11.2 mmol). The mixture wasstirred at −78° C. for 1 h and then poured onto solid carbon dioxide (5g) in THF (50 ml). The mixture was allowed to warm to room temperature.Water was added (200 ml) and the mixture was extracted with diethylether (3 times). The aqueous layer was acidified by addition ofconcentrated HCl and extracted with chloroform (3 times). The combinedchloroform extracts were washed with water, dried over MgSO₄, andconcentrated in vacuo to give a white solid; yield 1.2 g (73%).

Example C 4-Cyano-2-methylbenzoic acid

4-Bromo-3-methylbenzonitrile (2.0 g, 10.2 mmol) was reacted followingthe method of Example B to give a yellow solid which was triturated withhexane and filtered off; yield 0.96 g (59%).

Reagents corresponding to fragments A, B and C were combined to give thespecific Examples as detailed below.

Example 11-(2-Methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-Proline-N,N-dimethylamide

1A.2-Methyl-4-((2,3,4,5-tetrahydro-1H-benzo[b]azepine)-1-carbonyl)-benzonitrile

To a solution of 2,3,4,5-tetrahydro-1H-benzo[b]azepine (0.80 g, 5.44mmol) in dichloromethane (50 ml) were added 4-cyano-3-methylbenzoic acid(0.96 g, 5.95 mmol), triethylamine (0.60 g, 5.95 mmol),4-(dimethylamino)pyridine (0.73 g, 5.95 mmol) and WSCDI (1.24 g, 6.48mmol). The mixture was stirred at reflux for 18 h, cooled and evaporatedin vacua. The residue was partitioned between EtOAc and 1M KHSO₄. Theorganic layer was washed with saturated sodium bicarbonate solution andbrine, dried over MgSO₄, and concentrated in vacuo. The crude materialwas purified by flash chromatography on silica (eluant EtOAc:pet. ether30:70); yield 1.10 g (70%).

1B.1-(4-(Aminomethyl)-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepinehydrochloride

To a degassed solution of the cyanobenzazepine of Example 1A (1.10 g,3.79 mmol) in methanol (50 ml) were added concentrated hydrochloric acid(0.98 ml, 11.3 mmol) and 10% palladium on carbon (0.80 g). Hydrogen gaswas bubbled through the mixture for 5 h at room temperature. Thecatalyst was removed by filtering through a pad of celite and thefiltrate was evaporated; yield 1.23 g (98%).

1C.1-(2-Methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl-L-proline-N,N-dimethylamide

To a solution of the amine of Example 1B (0.10 g, 0.302 mmol) in DMF (10ml), under a nitrogen atmosphere, were added N,N-diisopropylethylamine(43 mg, 0.332 mmol) and carbonyl diimidazole (0.074 g, 0.453 mmol). Themixture was stirred at room temperature for 40 minutes. A solution ofproline-N,N-dimethylamide (0.107 g, 0.756 mmol) in DMF (1 ml) was added.The mixture was stirred at room temperature for a further 16 hr. Thesolvent was removed in vacuo and the crude material was purified byflash chromatography on silica (eluant methanol:dichloromethane 5:95);yield 0.115 g (82%).

¹H NMR (CDCl₃): δ 1.35–1.55 (1H, m), 1.74–2.10 (3H, m), 2.11 (3H, s),2.17–2.35 (1H, m), 2.60–2.82 (2H, m), 2.86 (3H, s), 2.90–3.14 (2H, m),3.05 (3H, s), 3.26 (1H, dd, J−14.9 & 7.2 Hz), 3.40–3.53 (1H, m),3.64–3.84 (1H, m), 4.03–4.19 (1H, m), 4.29–4.42 (1H, m), 4.55–4.68 (1H,m), 4.74–4.81 (1H, m), 4.85–4.98 (1H, m), 6.58 (1H, d, J=7.7 Hz),6.75–6.89 (2H, m), 6.91–7.06 (3H, m), 7.16 (1H, d, J=6.5 Hz), 7.93–8.03(1H, m) ppm.

M.S.: calc m/e=462.26; found [M+H]⁺=463.2.

Example 2(4R)-4-Hydroxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide

2A. L-trans-4-Hydroxyproline-N,N-dimethylamide hydrochloride

To a solution of BOC-hydroxyproline (2.99 g, 13.89 mmol) indichloromethane (100 ml) were added N,N-diisopropylethylamine (3.7 ml,21.24 mmol), 4-(dimethylamino)pyridine (1.74 g, 14.24 mmol),dimethylamine hydrochloride (1.72 g, 21.09 mmol) and WSCDI (3.17 g,16.68 mmol). The mixture was stirred at room temperature for 30 hr. Themixture was diluted with dichloromethane (100 ml) and washed with 0.3MKHSO₄, saturated sodium bicarbonate solution and brine, dried overMgSO₄, and concentrated in vacuo to give a colourless gum. This crudematerial was taken up in 4N HCl/dioxan (50 ml) and stirred at roomtemperature for 1 hr and then concentrated in vacua. The residue wasazeotroped with toluene and diethyl ether to give a white solid; yield0.45 g (17%).

2B.(4R)-4-Hydroxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide

The amine of Example 1B (0.10 g, 0.302 mmol) was reacted with the amineof Example 2A (0.153 mg, 0.785 mmol) following the method of Example 1C.The product was purified by flash chromatography on silica (eluantchloroform:methanol:acetic acid 95:4:1); yield 0.95 g (66%).

¹H NMR (CDCl₃): δ 1.65–1.80 (2H, m), 1.85–2.00 (3H, m), 2.05–2.25 (1H,m), 2.10 (3H, s), 2.80–3.10 (3H, m), 2.85 (3H, s), 3.00 (3H, s),3.40–3.30 (1H, m), 3.45–3.55 (1H, m), 3.65–3.95 (1H, m), 4.00–4.10 (1H,m), 4.30–4.55 (1H, m), 4.91 (1H, t, J=7.7 Hz), 5.15–5.30 (1H, m),6.10–6.20 (1H, m), 6.55–6.65 (1H, m), 6.85–7.50 (5H, m) ppm.

M.S.: calc m/e=478.26; found [M+H]⁺=479.2.

Examples 3–116

The additional examples set out in the following Tables were preparedusing analogous methods.

Example No R/S V² X Y [M + H]⁺ 3 S H H₂ OMe 436.4 4 R H H₂ OMe 436.2 5R/S OPh O OH 528.3 6 R/S OPh O NMe₂ 555.3

Example No R¹ R² V¹ V² X Y [M + H]⁺ 7 H Me H H O OtBu 492.5 8 H Me H H OOH 436.3 9 H Me H OH O OMe 466.0 10 H Me H OAc O NMe₂ 521.0 11 H Me ═O ONMe₂ 477.3 12 H Me H OH O OEt 480.2 13 H Me H OCOcC₃H₅ O NMe₂ 547.3 14 HMe H OMe O NMe₂ 493.5 15 H Cl H H O NMe₂ 483.4 16 H Me H H S NMe₂ 479.217 H Me H H O NMeEt 477.2 18 H OMe H H O NMe₂ 479.2 19 H Me H OMe O OMe480.2 20 H Me H H O OiPr 478.2 21 H Me H OH O OH 452.1 22 H Me H OBn OOiPr 584.2 23 H Me H OH O OiPr 494.1 24 H Me H OBn O NMe₂ 569.2 25 Me HH H O NMe₂ 463.2 26 H Me H OMe O OH 466.2 27 Cl H H H O NMe₂ 483.1 28 HEt H H O NMe₂ 477.3 29 H Cl H H S NMe₂ 499.2 30 H Cl H OBn O NMe₂ 589.231 H Cl H OH O NMe₂ 499.2 32 H Me H OEt O NMe₂ 507.3 33 H Me Br H O NMe₂541.1 34 H Me H Cl O OMe 484.1 35 H Me F F O NMe₂ 499.2 36 H Me H Cl OOH 470.1 37 H Me H N₃ O NMe₂ 504.3 38 H Me H Cl O NMe₂ 497.2 39 H Me HOtBu O NMe₂ 535.3 40 H Me Cl H O NMe₂ 497.2 41 H Me H OPh O OMe 542.3 42H Me H F O OMe 468.3 43 H Me H F O OH 454.4 44 H Me H F O NMe₂ 481.3 45H Me H NHBn O NMe₂ 568.0 46 H Me OMe OMe O OMe 510.3 47 H Me OMe OMe OOH 496.2 48 H Me OMe OMe O NMe₂ 523.3

Example No R² V² X [M + H]⁺ 49 Cl H O 489.1 50 Me H O 469.2 51 Me OH O485.0 52 Cl OMe O 519.3 53 Me OMe O 499.3 54 Cl OMe S 535.1

Example No R³ V² W¹ X [M + H]⁺ 55 H H S O 479.4 56 H OH S O 495.0 57 H HS S 495.1 58 Me H O O 477.2 59 H OBn S O 585.2 60 H OBn O S 585.0

Example No A¹⁶ A¹⁷ R² V² [M + H]⁺ 61 NEt CH₂ Me OMe 522.4 62 NH CH₂ MeOMe 494.3 63 CH₂ NiPr Me OMe 536.4 64 CH₂ NH Me OMe 494.5 65 O CH₂ ClOMe 515.2 66 CH(OH) CH₂ Me H 479.2

Example No A V² [M + H]⁺ 67

H 518.0 68

H 532.2 69

H 527.0 70

H 516.1 71

H 515.0 72

H 514.6 73

H 513.7 74

H 502.1 75

H 500.7 76

OH 547.9 77

OH 517.6 78

OH 546.3 79

H 517.2 80

OBn 619.2 81

OMe 543.4 82

OMe 544.3 83

OMe 549.2 84

OMe 548.2 85

OMe 562.1 86

OMe 590.2

Example No V¹ V² X Y [M + H]⁺ 87 H H S NMe₂ 516.2 88 H OBn O NMe₂ 606.389 H OH O NMe₂ 507.3 90 H OMe O NMe₂ 530.3 91 —OCH₂CH₂O— O OMe 545.3 92OMe OMe O OMe 547.3 93 —OCH₂CH₂O— O NMe₂ 558.3 94 —SCH₂CH₂S— O NMe₂590.2

Example No R² V¹ V² X Y [M + H]⁺ 95 Me H OH O NMe₂ 516.1 96 Me H H SNMe₂ 516.2 97 Me H OMe O NMe₂ 530.4 98 Me —OCH₂CH₂O— O OMe 545.3 99 Me—OCH₂CH₂O— O OH 531.3 100 Me —OCH₂CH₂O— O NMe₂ 558.3 101 Cl H H O NMe₂551.5 102 Me H OMe O NEt₂ 558.3 103 Me H OMe O

570.3 104 Me H OMe S NMe₂ 546.2

Example No A¹⁰ R² V² X [M + H]⁺ 105 O Me H O 519.3 106 NMe Me H O 532.3107 NMe Me OH O 548.1 108 NMe Me OBn O 638.2 109 NMe Me OMe O 562.3 110O Me OMe O 549.2 111 NMe Me Cl O 566.2 112 NMe Me OMe S 578.2 113 O ClOMe O 569.1 114 O Me OMe S 565.2 115 O Cl OMe S 585.1 116 NH Me OMe O548.2

Example 117

In Vitro Biological Characterisation

The compounds of the invention are selective agonists at the V₂receptor. In standard radio-ligand displacement assays, the compoundsall give K₁ values below 10 μM for the V₂ receptor.

Example 118

In Vivo Biological Characterisation

The Brattleboro rat is recognised model for vasopressin deficiency (fora review see FD Grant, “Genetic models of vasopressin deficiency”, Exp.Physiol. 85, 203S–209S, 2000). The animals do not secrete vasopressinand consequently produce large volumes of dilute urine. Compunds of theinvention were administered to Brattleboro rats (0.1–10 mg/kg p.o. inmethylcellulose. Urine was collected hourly and volumes were comparedwith control animals. Animals had free access to food and waterthroughout the experiment. Representative results are given in theTable. Results for Desmopressin are given for comparison.

% inhibition of urine output Compound of Example Dose (at 1 hour) 1 1mg/kg 82 14 1 mg/kg 84 52 1 mg/kg 90 54 1 mg/kg 68 85 1 mg/kg 63 90 1mg/kg 60 101 1 mg/kg 74 104 1 mg/kg 81 109 1 mg/kg 73 110 1 mg/kg 80 1121 mg/kg 75 114 1 mg/kg 85 115 1 mg/kg 88 0.1 mg/kg 37 Desmopressin 1mg/kg 100 10 mg/kg 100

Example 119

Pharmaceutical Composition for Tablet

Tablets containing 100 mg of the compound of Example 1 as the activeagent are prepared from the following:

Compound of Example 1 200.0 g Corn starch 71.0 g Hydroxypropylcellulose18.0 g Carboxymethylcellulose calcium 13.0 g Magnesium stearate 3.0 gLactose 195.0 g Total 500.0 g

The materials are blended and then pressed to give 2000 tablets of 250mg, each containing 100 mg of the compound of Example 5.

The foregoing Examples demonstrate that compounds within the scope ofthe invention are readily prepared using standard chemical techniques,and that these compounds have the biological properties that would beexpected of V₂ receptor agonists. In particular, the compounds arepotent antidiuretics in an animal model of vasopressin deficiency. Thusit is clear that they may be useful in the treatment of human diseasesthat are currently treatable with Desmopressin, such as central diabetesinsipidus, nocturnal enuresis and nocturia. It has further beensuggested that antidiuretics such as Desmopressin may be useful incertain types of urinary incontinence. These arguments would also extendto the compounds of the present invention.

Desmopressin is also used in the treatment of certain coagulationdisorders. There is good evidence to suggest that this action is alsomediated through the V₂ receptor (see for example J E Kaufmann et al.,“Vasopressin-induced von Willebrand factor secretion from endothelialcells involves V₂ receptors and cAMP”, J. Clin. Invest. 106, 107–116,2000; A Bernat et al., “V₂ receptor antagonism of DDAVP-induced releaseof hemostasis factors in conscious dogs”, J. Pharmacol. Exp. Ther. 282,597–602, 1997), and hence it would be expected that the compounds of thepresent invention should be useful pro-coagulants.

The scope of the present invention is further defined in the followingclaims.

1. A compound according to formula 1, or a pharmaceutically acceptablesalt thereof,

wherein: A is a benzazepine ring as follows

and wherein A¹⁶ and A¹⁷ are both CH₂; Z is —CH═CH—; V¹ and V² are bothH, OMe or F, or one of V¹ and V² is OH, OMe, OBn, OPh, O-acyl, Br, Cl,F, N₃, NH₂, NHBn or NH-acyl and the other is H, or V¹ and V² togetherare ═O, —S(CH₂)_(p)S— or —O(CH₂)_(p)O—; W¹ is either O or S; X¹ and X²are both H, or together are ═O or ═S; Y is OR⁵ or NR⁶R⁷; R¹, R², R³, andR⁴ are independently selected from H, lower alkyl, lower alkyloxy, F, Cland Br; R⁵ is selected from H and lower alkyl; R⁶ and R⁷ areindependently selected from H and lower alkyl, or together are—(CH₂)_(n)—; n=3, 4, 5 or 6; and p=2 or
 3. 2. A compound according toclaim 1, or a pharmaceutically acceptable salt thereof, wherein one ofR¹ and R² is Cl or Me and the other is H, and both R³ and R⁴ are H.
 3. Acompound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein one of V¹ and V² is OMe or OBn and the other is H.
 4. Acompound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein X¹ and X² together are ═O and Y is NR⁶R⁷.
 5. A compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof,which is

wherein W¹ is either O or S; one of R^(a) and R^(b) is Cl or methyl andthe other is H; R^(c) is methyl or benzyl; R⁶ and R⁷ are independentlyselected from H and lower alkyl, or together are —(CH₂)_(n)—; and n is3, 4, 5 or
 6. 6. A compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, which is

wherein W¹ is either O or S; one of R^(a) and R^(b) is Cl or methyl andthe other is H; R^(c) is methyl or benzyl; and R⁶ and R⁷ areindependently selected from H and lower alkyl, or together are—(CH₂)_(n)—; and n is 3, 4, 5 or
 6. 7. A compound according to claim 1,or a pharmaceutically acceptable salt thereof, wherein V¹ and V² areboth H.
 8. A compound according to claim 7, or a pharmaceuticallyacceptable salt thereof, wherein X¹ and X² together are ═O and Y isNR⁶R⁷.
 9. A compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, which is

wherein W¹ is either O or S; one of R^(a) and R^(b) is Cl or methyl andthe other is H; R⁶ and R⁷ are independently selected from H and loweralkyl, or together are —(CH₂)_(n)—; and n is 3, 4, 5, or
 6. 10. Acompound according to claim 1, or a pharmaceutically acceptable saltthereof, which is

wherein W¹ is either O or S; one of R^(a) and R^(b) is Cl or methyl andthe other is H; R⁶ and R⁷ are independently selected from H and loweralkyl, or together are —(CH₂)_(n)—; and n is 3, 4, 5 or
 6. 11. Acompound according to claim 1, which is selected from the groupconsisting of1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide,(4R)-4-hydroxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide,(4R)-1-(3-chloro-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-4-methoxy-L-proline-N,N-dimethylamide,(4R)-1-(2-chloro-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-4-methoxy-L-proline-N,N-dimethylamide,(4R)-4-benzyloxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide,(4R)-4-methoxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide,(4R)-4-methoxy-1-(3-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide,or a pharmaceutically acceptable salt thereof.
 12. A pharmaceuticalcomposition which contains active agent selected from compounds andpharmaceutically acceptable salts according to claim
 1. 13. A method oftreatment of a condition selected from the group consisting of nocturnalenuresis, nocturia and central diabetes insipidus, which methodcomprises the administration to a person in need of such treatment of aneffective amount of a composition according to claim
 12. 14. A methodfor the control of urinary incontinence, which method comprises theadministration to a person in need of such treatment of an effectiveamount of a composition according to claim
 12. 15. A method of treatmentaccording to claim 14, wherein the treatment results in voidingpostponement.
 16. A method of treatment of bleeding disorders, whichmethod comprises the administration to a person in need of suchtreatment of an effective amount of a composition according to claim 12.